bms-536924 and Insulin-Resistance

Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control-diet-fed mice (2.2 ± 0.1 and 2.67 ± 0.15 μM/s, respectively). Moreover, glucose clearance rate was negatively correlated with V

Topics: Androstadienes; Animals; Area Under Curve; Benzimidazoles; Blood Glucose; Diet, High-Fat; Dopamine; Dopaminergic Neurons; Electrochemistry; Electrodes; Enzyme Inhibitors; Fasting; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Pyridones; Receptor, Insulin; Signal Transduction; Wortmannin

Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.

Topics: Alloxan; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Evaluation, Preclinical; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Metformin; Protein Kinase Inhibitors; Pyridones; Receptor, IGF Type 1; Treatment Outcome